Stable epinephrine suspension formulation with high inhalation delivery efficiency

ABSTRACT

A stable suspension aerosol formulation of epinephrine is suitable for administration through inhalation comprising a therapeutically effective amount of epinephrine, hydrofluorocarbon propellant, co-solvent, surfactant, and antioxidant. The suspension aerosol formulation further comprises [pre-] pre-micronized epinephrine suspended in an alcohol/surfactant solution with hydrofluoroalkane propellant. The suspension formulation provides a highly efficient delivery of drug microparticles into the respirable region of patients&#39; lungs and has the following advantages: lower dosage requirement, minimum alcohol content, with less impurities generated during storage, improved efficacy and safety, and exhibits no ozone depleting potential compared to a formulation containing chlorofluorocarbon.

RELATED APPLICATION

This application is a continuation in part of and claims the benefit ofpriority to U.S. patent application Ser. No. 11/200,634 filed Aug. 11,2005 now abandoned entitled “Suspension Formulation ContainingEpinephrine and Hydrofluoroalkane Propellant”, the disclosure of whichis incorporated herein by reference.

TECHNICAL FIELD

The invention generally pertains to aerosol formulations for thedelivery of medications suitable for administration via the respiratorytract. More particularly, the present invention pertains to a stablesuspension formulation containing epinephrine, or its salt forms, andhydrofluoroalkane propellant for use in a metered dose inhaler, withhigh inhalation delivery efficiency.

BACKGROUND ART

Medications for the treatment of respiratory disorders are commonlyadministered by inhalation through the mouth or nose in an aerosolformulation. As with any other delivery method, safety, toxicity andbioavailability, are the main concerns. The inhalation route can providesuperior advantages for the treatment of pulmonary diseases, as comparedwith other means of administration such as oral or injection. Injectionis the most effective method of administration to a patient's bloodstream, however it is a painful administration procedure, and systemicside effects may occur from the unwarranted spread of drug moleculessuch as steroids and beta-blockers. While oral intake is the preferredalternative for drug administration, it often requires large doses ofthe medication in order to be effective, which can result in unwantedside effects. Drug delivery by inhalation can effectively deposit amedication locally at a targeted therapeutic site, thereby providingrapid onset, a lower dosing requirement and decreased incidence of sideeffects.

One of the most widely used devices to deliver a formulation through theinhalation method for the treatment of pulmonary disorders is a metereddose inhaler (MDI). The MDI is widely used for the delivery ofbronchodilator type products for the treatment of respiratory disorderssuch as Chronic Obstructive Pulmonary Disease (COPD) and asthma. The MDIhas gained popularity since its introduction decades ago, mainly becauseadministration is convenient and practical. Additionally, the MDI iseasy to use, portable, capable of multiple dose delivery, low cost,provides minimal loss of drug within the device at the time ofadministration, and is a reliable and efficient method of drug deliveryto a targeted area of the patient's lungs.

Prior art metered dose inhaler formulations have historically containedchlorofluorocarbon (CFC) as propellants to deliver doses of medicationto a patient's lungs. However, CFCs have been associated with thedegradation of the ozone layer. Depletion of the ozone layer causes anincrease of UV light exposure, which is responsible for numerous healthproblems such as increased incidence of skin cancer, premature aging ofthe skin, cataracts/eye damage and suppression of the immune system. Theuse of CFC's is being phased out as part of the agreement of theMontreal protocol Exceptions have been made for certain uses that arenecessary for health and safety, which include MDIs for pharmaceuticaluse These types of products will be gradually phased out as substitutesbecome available.

The phasing out of CFCs has led to a flurry of development activitiesfor alternative means of pulmonary drug delivery without the use of CFCpropellants. One previous alternative is the use of nebulizers. Anebulizer is pressurized by an oxygen tank or oil free compressed airsource for the purpose of vaporizing a liquid medication into a finemist that is suitable for delivery via the respiratory tract without theuse of CFCs. However, nebulizers are expensive and inconvenient forpatients because there are problems with dosing uniformity, andnebulizers require a power supply for operation, are cumbersome andrequire a longer time for drug delivery. A nebulizer is mainly used inan emergency room or for children and elderly patients who cannotoperate an MDI themselves.

Another alternative to CFCs that is gaining popularity is a dry powderinhaler (DPI). A DPI has several advantages as it contains no propellantand is breath activated, thus eliminating the need to synchronizeinhalation with actuation. However, DPIs do present formulationchallenges for delivering micrograms of drug molecules uniformly fromdose to dose. A micronized drug has to be mixed with a coarse carriersubstance such as lactose, which can cause airway irritation in someasthmatic patients.

Over the years improvements have been made to the drug delivery systems,such as multidose DPIs and more versatile nebulizers that increaseconvenience and ease of use to patients. However, the advantages andsuperiority of a MDI remain unchallenged, which is the reason that MDIsremain as the most popular and widely used inhalation delivery device.Thus, reformulation of CFC based medicinal aerosols using a MDI appearsto be the best solution. The phase out of CFCs has made this an urgentmatter, which has also turned out to be an opportunity to improve theperformance of MDIs.

Hydrofluoroalkane (HFA) propellants have emerged as the best alternativeto replace CFC propellants in a MDI for pharmaceutical uses. HFA-134awith chemical formula 1,1,1,2-tetrafluoroethane, and HFA-227 withchemical formula 1,1,1,2,3,3,3-heptafluoropropane are considered themost suitable alternative propellants. The development of a newformulation utilizing HFA has proven to be a difficult challenge becausethis propellant tends not to function with CFC compatible excipients dueto differences in the chemical and physical properties of these twopropellants. Thus, there is a necessity to develop a new formulationthat provides an effective MDI formulation utilizing HFA propellant.

Epinephrine is commonly used as a bronchodilator in the treatment ofacute bronchial asthma. Currently, inhalable Epinephrine is onlyavailable in CFC form under the name Primatene® manufactured byArmstrong Pharmaceuticals, Inc. Primatene® is a CFC/alcohol solution ofepinephrine. It is supplied with a glass bottle because of its low pHdue to hydrochloric acid and nitric acid in the CFC formulation.Historically, CFC based MDI formulations with Epinephrine have a problemof low respirable fractions or drug delivery efficiency, and high throatdeposition requiring large drug doses to obtain therapeutic efficacy. Inaddition, epinephrine formulation is easily oxidized which can cause theformulation to become unstable. According to Analytical Profiles of DrugSubstances, Vol. 7, p. 213, “Since epinephrine is an o-diphenolcontaining a hydroxyl group in the α position, it is a strong reducingagent. As such, it is easily oxidized by such oxidizing agents asmolecular oxygen. Oxidation of epinephrine by molecular oxygen can alsoresult in formulation of a brownish insoluble material of indefinitestructure.”

Applicants have now discovered a new epinephrine suspension formulationwith improved formulation characteristics that solves prior art problemsby eliminating the use of CFCs and adding an antioxidant to produce astable formulation that exhibits a significantly higher drug depositionin the respirable region of a patient's lungs.

A search of the prior art reveals numerous patents for the preparationof MDI formulations that contain no CFC propellant or contain HFApropellant. However, none of the prior art patents possess the noveltyof the instant invention, which introduces a high efficiency stable MDIsuspension formulation containing epinephrine or its salt forms with HFAas the propellant for the treatment of asthma, COPD and otherrespiratory disorders.

SUMMARY OF THE INVENTION

The present invention discloses a high efficiency aerosol suspensionformulation that is suitable for administration by inhalation utilizinga metered dose inhaler (MDI). The formulation comprises atherapeutically effective amount of epinephrine or its salt form for thetreatment of acute bronchial asthma, chronic obstructive pulmonarydiseases and other respiratory disorders. The medication is provided ina suspension formulation that is suitable for delivery in a MDI andessentially consists of micronized epinephrine particles suspended in alow concentration of surfactant and co-solvent solution inhydrofluoroalkane propellant.

The UFA propellant typically consists of 1,1,1,2-tetrafluoroethane(HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), or a mixture ofthe two. The preferred surfactants are sorbitan oleates and thepreferred co-solvent is ethanol, both of which are present in an amountsufficient to prevent agglomeration or flocculation of the drugparticles and to maintain the physical stability of the suspension. Asmall amount of antioxidant is added to the formulation to minimizeimpurity generation through oxidation of epinephrine and to ensure thestability of the formulation during storage and use by patients.

The formulation of the present invention provides the followingadvantages compared to the prior art epinephrine formulation:

-   -   (1) the Proposed Epinephrine HFA suspension formulation contains        no CFC propellant so that it fulfills the requirements of the        Montreal protocol for environmental protection;    -   (2) the proposed HFA formulation eliminates the need for        hydrochloric acid and nitric acid in the CFC formulation, which        allows a metal container to be used, thus, eliminating any        possibility of broken or even explosive events due to the glass        container and is therefore safer for patients;    -   (3) the proposed HFA formulation has a significantly reduced        amount of alcohol which minimizes leaching alcohol-soluble toxic        material from the inhalation valves, and will significantly        reduce the risk that a patient exhibits a false positive blood        alcohol test which may occur if the patient just utilized the        current epinephrine inhalation with a high percentage of alcohol        and happens to be subjected to a breath alcohol analyzer;    -   (4) the proposed epinephrine HFA formulation significantly (39        times) reduces the impurities generated due to oxidation of        epinephrine during storage and usage by patients, which provides        a basis for the drug to meet storage requirement of good        manufacturing practice (GMP), and also reduces any risks of        adverse events caused by a higher level of impurities;    -   (5) the proposed epinephrine HFA formulation substantially        improves drug delivery to the targeted therapeutic area of the        lung, and thus requires a lower dose to produce similar        efficacy, which will in turn, reduce the possibility of adverse        events of patients caused by a higher dose.    -   (6) For this proposed epinephrine HFA formulation, the particle        size distribution of epinephrine is pre-determined by using        pre-micronized epinephrine so that the particle size is        well-controlled and its quality is stable and reliable per the        requirements of GMP.

In view of the above disclosure, the primary object of the invention isto provide a stable inhalable epinephrine suspension formulation that iscapable of efficiently delivering drug molecules to a therapeutic sitewith improved efficacy and safety.

Another object of the invention is to provide a suspension formulationcontaining epinephrine and HFA propellant that is suitable for deliveryin an MDI and that exhibits a uniform dosing level reproducible over thelife of the inhaler.

It is also an object of the invention to provide an inhalableepinephrine suspension aerosol formulation for delivery to the pulmonaryair passages that is free of CFC propellant with no ozone depletionpotential.

These and other objects and advantages of the present invention willbecome apparent from the subsequent detailed description of thepreferred embodiment and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a chart showing the impurity level for epinephrineformulations with and without antioxidant after three (3) monthsstorage.

FIG. 2 is a chart showing a comparison of respirable delivery of variousinhalable epinephrine formulations.

BEST MODE FOR CARRYING OUT THE INVENTION

The best mode for carrying out the invention is presented in terms of apreferred embodiment for a therapeutically effective amount of drugparticles in a suspension aerosol formulation suitable for inhalationdelivery using an MDI that is free of CFC. The aerosol formulation ispresented in the form of a suspension comprising micronized epinephrineparticles suspended in a low concentration of alcohol-surfactantsolution with HFA propellant suitable for administration by inhalation.The epinephrine particles in the formulation are pre-micronized toachieve a pre-determined particle size distribution. The formulation isindicated for the treatment of asthma, chronic obstructive pulmonarydisease and other respiratory disorders. The suspension formulation ofthe present invention provides a highly efficient delivery of medicationto the therapeutic region of the lungs, and the formulation of themedication is more stable and has less impurities than the productcurrently marketed.

The preferred medicament in the formulation of the present invention isepinephrine free base in an amount effective to exert the intendedtherapeutic action through delivery of one or more metered volumes ofthe formulation. The amount of micronized epinephrine in the formulationranges from 0.10% to 0.50% w/w relative to the total weight of theformulation.

The formulation of the present invention further comprises a HFApropellant as the energy source to deliver the drug molecules to thelung. The HFA propellant can be selected from the group consisting of1,1,1,2-tetrafluoroethane, which is also known as HFA-134a, and1,1,1,2,3,3,3-heptafluoropropane, which is also known as HFA-227, or amixture thereof. The preferred hydrofluoroalkane propellant is HFA-134ain an amount ranging from 98% to 99% w/w relative to the total weight ofthe aerosol formulation.

A co-solvent is added into the formulation of the present invention tohelp solubilize the surfactant and to improve the dispersioncharacteristics of the micronized epinephrine particles. The co-solventutilized in the formulation can be selected from the group consisting ofethyl alcohol, isopropyl alcohol, propylene glycol, ethylene glycol,propane, butane, isobutane, pentane, dimethyl ether, diethyl ether andthe like. Preferably, the co-solvent selected is ethanol. The ethanol ispresent in the formulation in an amount ranging from 0.5% to 1.5% w/w ofthe total weight of the formulation. This amount is substantially lesscompared to the prior art epinephrine formulation from the current CFCformulation Primatene®, and the epinephrine HFA solution formulation(application Ser. No. 11/052,734) which contains 34%, and 20%-30%alcohol respectively. The low amount of co-solvent provides asignificant advantage because a high percentage of ethanol has anegative effect on drug delivery efficiency by increasing the dropletsizes of the formulation during delivery. Thus, it is essential to haveonly a minimum amount of alcohol in the formulation to produce the fineparticle mists that are able to reach the therapeutic region of thelungs upon delivery. The low amount of alcohol provides an additionaladvantage as it minimizes container component leaching, which reducesthe amount of potentially toxic compounds (extractables) leached fromthe inhaler valve and, gasket into the formulation.

The epinephrine suspension formulation disclosed in the presentinvention is neutral and allows the use of a metal container and valveto eliminate any potential unsafe events, such as broken glass or evenexplosive containers, and also provides cost reduction and ease ofmanufacture.

A small amount of surfactant, preferably less than 0.05 w/w of the totalweight of the formulation, is added to provide improved solutionproperties. The surfactant can be selected from the group consisting ofoleic acid, lecithin and sorbitan oleates, e.g., sorbitan mono-oleateand sorbitan trioleate. The preferred surfactant is a sorbitan oleatesuch as polysorbate 80. The surfactant is included in the formulation toimprove the physical stability of the formulation and ensure consistentdelivery of medication from the MDI by coating the microparticles,which, in turn, prevents agglomeration of the particles, preventsadhesion of the particles to container walls, and provides lubricationfor valve components in the MDI.

A small amount of antioxidant, preferably less than 0.05% w/w of thetotal weight of the formulation, is also added to the formulation.Epinephrine is one product that is readily oxidized. Thus, the presenceof an antioxidant in the formulation is critical to prevent oxidationand maintain stability of the medication to produce a highly efficientepinephrine formulation. Certain antioxidants that are not readilysoluble in the formulation might not be appropriate to be used in thepresent application. The antioxidant that can be used in the presentformulation can be selected from the group consisting of thymol,tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, propyl gallate, sodium metabisulfite, citric acid, andsodium sulfite. The preferred antioxidant is Thymol.

Table 1 and FIG. 1 shows the impurity profiles of the presentepinephrine HFA formulation with and without the antioxidant thymol. Asshown in Table 1, the total impurities after three (3) months of storageat 40° C. for the epinephrine formulation with and without thymolincreases 11% and 433%, respectively, compared to the total impuritieslevel of the same formulations at zero-time. These data represent thatthe epinephrine formulation with antioxidant can reduce the totalimpurities 39 times compared to the formulation without an antioxidant.The high level of impurities during long-term storage in the formulationwithout the antioxidant thymol can cause the formulation to becomeunstable, fall out of specification, and make the formulationpractically not usable.

TABLE 1 Impurity Profiles of Epinephrine/HFA Formulation with andwithout Thymol Relative Impurities, as Percentage of the EpinephrinePeak Changes of Potency Impurity Impurity Impurity Total Δ of TotalTotal Formulation Lot No. mcg/inh Time #1 ^(b)) #2 ^(c)) #3 ^(d))Impurities Impurities Impurities A1 0800208 60 Zero-Time 0.030 0.0000.000 0.030 — — with 3 Months ^(a)) 0.033 0.000 0.000 0.033 0.003  11%Thymol A1 0800608 60 Zero-Time 0.030 0.000 0.000 0.030 — — Without 3Months ^(a)) 0.043 0.030 0.087 0.160 0.130 433% Thymol ^(a)) Storageconditions: 40 C., 75% Relative humidity. ^(b)) Impurity-1: EpinephrineSulfonic Acid, relative retention time 0.6 minutes; ^(c)) Impurity-2:Unknown, relative retention time 2.4 minutes; ^(d)) Impurity-3: Unknown,relative retention time 4.2 minutes.

The therapeutic efficacy of an aerosol formulation is determined by theamount of drug particles that are able to penetrate into a patient'sdeeper lung region. Fine particle fraction (FPF) is a measure of thepercentage of drug molecules leaving the MDI that is deposited in therespirable regions of a patient's lungs. A higher fine particle fractionindicates improved delivery efficiency due to a significant decrease inthroat deposition. Having a higher fine particle fraction allows a loweramount of total drug dose needed to achieve equivalent therapeuticbenefits. Applicants have discovered that the suspension formulation ofthe present invention is capable of producing a significantly higherfine particle fraction compared to the prior art formulations bysuspending the pre-micronized drug particles in the propellant. Thesuspension formulation can be formulated with a lower amount of drugconcentration and only requires a small amount of co-solvent becausesolubility of epinephrine is not necessary.

Most conventional solution formulations require a higher amount ofethanol to help solubilize the drug molecules. The high amount alcoholwill generate a significant number of larger particle droplets andreduce pulmonary delivery efficiency. The suspension formulation of thepresent invention contains pre-micronized epinephrine microparticleswith average particle size smaller than 10 μm, preferably 99% in weighthas a particle size less than 5 μm, which permits inhalation of asubstantially high percentage of the drug into a patient's lungs uponadministration. The small droplet/particle size will lead to lessaccumulation of the drug in the patient's throat and improve depositionin the alveolar region of the lung.

The preferred formulation of the current invention comprises ofpre-micronized epinephrine, with particle sizes less than 5 μm, in anamount ranging from 0.10% to 0.50% w/w, ethanol in an amount rangingfrom 0.5% to 1.5% w/w, HFA-134a propellant in an amount of 98% to 99%w/w, Polysorbate 80 in an amount less than 0.05% w/w, and Thymol in anamount less than 0.05% w/w. All of the weights disclosed are based onthe total weight of the formulation. The suspension formulation is ableto produce a significantly higher fine particle fraction compared withthe prior art formulations which allows more efficient delivery. This isachieved by suspending the drug microparticles in a surfactant-alcoholicsolution in hydrofluoroalkane propellant with the addition of a smallamount of an antioxidant, which creates a more uniform dispersion, lessagglomeration or sedimentation of the particles, improved stability andefficacy of the formulation.

Table 2 provides a comparison between five (5) proposed formulationswith different dosage strength of the Epinephrine HFA suspensionformulation and four (4) prior art HFA formulations. Notice that theformulation of the present invention contains a significantly loweramount of alcohol and includes the addition of an antioxidant andexhibits a significantly higher delivery efficiency.

An Andersen cascade impaction analysis coupled with a HPLC assay per USP<601>, Aerodynamic Size Distribution, was used to analyze the fineparticle fractions at different stages of the lung. An Andersen cascadeimpactor has nine stages simulating the various parts of the humanrespiratory system (the different regions of the lung). The nine stagecascade impactor utilizes jet stages, which enable classification ofaerosols from 9.0 micrometers (stage 0) to 0.4 micrometers (stage 7) at28.3 lpm, and allows drug particles to impact upon stainless steel oraluminum impaction plates. A filter located after the last stagecollects all particles smaller than 0.4 micrometers.

TABLE 2 Respirable Delivery Assessment of Epinephrine InhalationFormulations Type of Formulation This Application Prior Art LotNo/Reference No 0800208 0800909 0801209 0801009 0801109 11/052,73411/052,734 11/052,734 EB062409 Symbol of Formulation A1 A2 A3 A4 A5 P1P2 P3 P4 Formulation Epinephrine — — — — — — — — 0.3 Bitartrate, %Epinephrine, % 0.12 0.19 0.27 0.35 0.48 0.29 0.27 0.24 — HFA 134a, %42.98 98.78 98.70 98.62 98.49 74.36 75.38 77.41 — HFA 227, % 55.87 — — —— — — — 91.28 Ethanol, % 1.00 1.00 1.00 1.00 1.00 23 22 20 8.4 Oleicacid, % 0.015 — — — — — — — 0.02 Polysorbate 80, % — 0.02 0.02 0.02 0.02— — — — Thymol NF, % 0.01 0.01 0.01 0.01 0.01 — — — — Ascorbic Acid, % —— — — — 0.07 0.07 0.07 — HCl, % — — — — — 0.82 0.76 0.68 — PurifiedWater, % — — — — — 1.46 1.52 1.6 — Total, % 100.00 100.00 100.00 100.00100.00 100.00 100.00 100.00 100.00 Cascade Ad/IP/H * 23.7 26.9 40.0 54.571.6 75.5 72.0 59.1 68.7 Impactor Data Stage 0 0.5 0.4 0.8 1.07 1.62 4.84.6 2.9 2.3 Stage 1 0.5 0.6 1.3 1.7 3.2 1.3 1.5 0.8 1.3 Stage 2 0.9 1.12.6 4.1 6.7 0.8 0.8 0.5 2.8 Stage 3 4.1 5.9 12.4 19.9 28.9 4.0 3.8 2.57.5 Stage 4 11.0 20.6 29.6 39.4 54.5 8.2 8.5 6.3 5.1 Stage 5 15.0 28.132.4 40.5 46.2 9.2 11.0 7.5 2.0 Stage 6 1.5 3.6 3.3 3.8 5.5 3.0 3.5 3.10.6 Stage 7 0.4 0.7 0.7 0.8 1.0 1.2 1.4 1.3 0.3 Stage F 0.7 1.6 1.6 2.32.6 4.0 1.7 6.3 1.2 Total Total, mcg 58.2 89.4 124.8 168.1 221.8 112.0108.8 90.3 91.9 Respirable S3-S7, mcg 32.0 58.8 78.4 104.5 136.1 25.628.2 20.7 15.6 Delivery S3-S7, % 55% 66% 63% 62% 61% 23% 26% 23% 17%Statistical Analysis Average ± SD 61% ± 4.0% 22% ± 3.8% for Respirablep-value 0.000001 Delivery * Ad/IP/H : Adapter/Induction port/Head cone.

The drug particle analysis can be separated into three categories:

-   -   Drug deposited in the mouth or throat, which is indicated by        Ad/IP/H area in the impactor;    -   Drug that penetrates through the throat but collect in the upper        airways due to their relatively large particle size, which is        represented by stage 0 to stage 2 in the impactor;    -   Drug with small particle size that is able to reach the        respirable regions of the lung or the effective therapeutic        regions, which is represented by stage 3 to stage 7 in the        impactor.

Table 2 summarizes the results from the Andersen impaction analysisshowing the deposition at different stages of the lung and providesside-by-side comparison between the current HFA suspension formulationswith the prior art HFA formulation.

As shown in Table 2, the Epinephrine HFA suspension formulation iscapable of delivering significantly higher drug concentration to therespirable region (Stage 3-7) of the instrument, which represents thepercentage of drug particles that are capable to deposit in therespirable region of the lungs.

Table 2 reveals that the proposed HFA suspension formulation can deliverup to 2.8 times, fine particle fraction (FPF) in Stage 3-7, compared tothe prior art HFA formulations. This occurrence is mainly due to theminimum co-solvent concentration and pre-determined particle sizedistribution in the present HFA suspension formulation, which allowsmore drug particles to be delivered and to penetrate deeper into thetherapeutic region of the lungs. The results from Andersen cascadeimpactor analysis can be seen more clearly in FIG. 2, which showsrespirable delivery of the different epinephrine formulations.

FIG. 2 clearly illustrates that the present epinephrine suspensionformulations, A1-A5, have an obviously higher percentage of medicationthat reach the respirable region of the lungs compared to the prior artHFA based epinephrine formulations, P1-P4. The mean percentages ofrespirable delivery of epinephrine are 61%±4.0% and 22%±3.8%,respectively, for this applied formulation and the prior artformulations.

A one-sided t-test for the following hypothesesHo X _(A) ≦X _(P)Ha X _(A) >X _(P)where X_(A) and X_(P) are pulmonary deliverable fine particle fractionof this applied epinephrine formulation and the prior art epinephrineformulation. The t-test for the above hypotheses obtained a p-value of0.000001, which is much smaller than 0.05. Thus, the above nullhypothesis Ho is rejected, and the alternative hypothesis Ha isaccepted. Therefore, the applied epinephrine suspension formulation candeliver significantly more respirable epinephrine than the prior artformulation.

A summary of comparison of the applied epinephrine suspensionformulation and the prior art formulation is provided in Table 3.

TABLE 3 Comparison of Applied Epinephrine Formulation with the Prior ArtThis Prior Art (Appl. # Formulation Application No 11/052,734) Note 1Type of Formulation Suspension True Solution 2 Epinephrine UsedPre-micronized — 3 Status of Epinephrine Solid particles Solute,Dissolved in Formulation 4 with antioxidant? Yes No 5 Increase of Total0.003% 0.130%   1:39 Impurities after 3- month storage at 40 C. 6Pulmonary Delivery   61%   22% 2.8:1 Efficiency of Epinephrine (%)

The examples and experiment provided are solely for illustrationpurposes and not meant to limit the invention in any way. While theinvention has been described in complete detail, it is not to be limitedto such details, since many changes and modifications may be made to theinvention without departing from the spirit and scope thereof. Hence, itis described to cover any and all modifications and forms, which maycome within the language and scope of the appended claims.

1. An aerosol formulation for use with a metered dose inhalercomprising: a. a suspension dosage form of pre-micronized epinephrinefree base, b. a pressure liquefied propellant comprising ahydrofluoroalkane present in an amount in a range of 98% or more w/wbased on the total weight of the formulation, c. a co-solvent selectedfrom the group consisting of ethyl alcohol, isopropyl alcohol, propyleneglycol, ethylene glycol, propane, butane, isobutene, pentane, dimethylether, and diethyl ether, the co-solvent being present in the aerosolformulation and the amount of the co-solvent being less than 2% w/wbased on the total weight of the formulation, d. a surfactant selectedfrom the group consisting of mono- or poly-sorbitan oleates, oleic acid,and lecithin, and e. an antioxidant selected from the group consistingof thymol, tocopherol, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, propyl gallate, citric acid, sodiummetabisulfite and sodium sulfite, the antioxidant being present in theformulation.
 2. The aerosol formulation as specified in claim 1, whereinsaid pre-micronized epinephrine free base is present in an amount in arange of 0.10% to 0.50% w/w based on the total weight of theformulation.
 3. The aerosol formulation as specified in claim 1, wherein99% in weight of said pre-micronized epinephrine free base has aparticle size in a range of less than 5 micrometers in diameter.
 4. Theaerosol formulation as specified in claim 1, wherein said liquefiedpropellant comprises a hydrofluoroalkane selected from the groupconsisting of 1,1,1,2-tetrafluoroethane (HFA-134A),1,1,1,2,3,3,3-heptafluoropropane (HFA-227), or a mixture thereof in anamount in a range of 98% or more w/w based on the total weight of theformulation.
 5. The aerosol formulation as specified in claim 1, whereinsaid co-solvent is ethanol in an amount in a range of 0.5% to 1.5% w/wbased on the total weight of the formulation.
 6. The aerosol formulationas specified in claim 1, wherein said surfactant is present in an amountof no more than 0.05% w/w based on the total weight of the formulation.7. The aerosol formulation as specified in claim 1, wherein saidantioxidant is present in an amount of no more than 0.05% w/w based onthe total weight of the formulation.
 8. The aerosol formulation asspecified in claim 1, wherein said formulation has a fine particlefraction which improves drug delivery efficiency and allows for a loweramount of total drug dosage to achieve therapeutic benefits as comparedto a formulation containing less than 98% hydrofluoroalkane.
 9. Anaerosol formulation for use with a metered dose inhaler comprising: a.pre-micronized epinephrine free base suspended in a surfactant-alcoholicsolution in an amount in a range of 0.1% to 0.50% w/w based on the totalweight of the formulation; b. hydrofluoroalkane propellant in an amountin a range of 98% or more w/w of the total weight of the formulation; c.an alcohol in an amount in a range of 0.5% to 1.5% w/w based on thetotal weight of the formulation; d. polysorbate in an amount of no morethan 0.05% w/w based on the total weight of the formulation; and e.thymol in an amount of no more than 0.05% w/w based on the total weightof the formulation, the thymol being present in the formulation, wherein99% in weight of said pre-micronized epinephrine free base has aparticle size of less than 5 micrometers in diameter.
 10. An aerosolformulation for use with a metered dose inhaler comprising: a suspensiondosage form of pre-micronized epinephrine free base; a pressureliquefied propellant comprising a hydrofluoroalkane present in an amountin a range of 98% or more w/w based on the total weight of theformulation; a co-solvent selected from the group consisting of ethylalcohol, isopropyl alcohol, propylene glycol, ethylene glycol, propane,butane, isobutane, pentane, dimethyl ether, diethyl ether and mixturesthereof, the co-solvent being present in the aerosol formulation and theamount of the co-solvent being less than 2% w/w based on the totalweight of the formulation; and a surfactant.
 11. The aerosol formulationas specified in claim 10, wherein the co-solvent is present in an amountin a range of 1% to less than 2% w/w based on the total weight of theformulation.
 12. The aerosol formulation as specified in claim 10,wherein the co-solvent is present in an amount less than or equal to 1%w/w based on the total weight of the formulation.
 13. The aerosolformulation as specified in claim 10, wherein the hydrofluoroalkane ispresent in an amount of 98% to 99% w/w based on the total weight of theformulation.